PREVENTIVE/THERAPEUTIC AGENT FOR ALZHEIMER'S DEMENTIA

Description

Technical Field

[0001] This invention relates to a novel preventive or therapeutic drug for Alzheimer-type dementia, and more specifically, to a preventive or therapeutic drug for Alzheimer-type dementia wherein an ω-3 polyunsaturated fatty acid is used in combination with a thyroid hormone.

Background Art

[0002] With the progress of aging of the society, number of patients suffering from dementia is ever more increasing. Dementia is the condition in which acquired intelligence has persistently declined by organic disorder of brain. Dementia has been classified into several types based on the pathogenesis and histopathology, and the most typical types are Alzheimer-type dementia and cerebrovascular dementia. Conceivably, these two types of dementia and the mixed type of these two constitute 80 to 90% of the entire dementia case.

[0003]  Alzheimer-type dementia is associated with atrophy of brain, and up to this moment, no drug has been found that can fundamentally treat this disease. The only commercially available pharmaceutical product with the indication for Alzheimer-type dementia is donepezil hydrochloride (trade name Aricept: manufactured by Eisai Co., Ltd.). This product, however, is indicated for "inhibition of the advance of dementia symptoms of slight or moderate Alzheimer-type dementia", and this product may not be sufficient in view of fundamental treatment of the disease.

[0004] Icosapentaenoic acid (also referred to as eicosapentaenoic acid, hereinafter abbreviated as EPA) which is a member of ω-3 polyunsaturated fatty acids is a polyunsaturated fatty acid extracted and purified from fish oil, and EPA is known for its effect of reducing serum lipids, suppressing platelet aggregation, and the like. In Japan, ethyl ester of this EPA is commercially available as a therapeutic drug for arteriosclerosis obliterans and a therapeutic drug for hyperlipidemia. EPA has been reported to retard advance of symptoms of Alzheimer-type dementia (see, for example, Non-patent document 1). This document discloses that, when the patients suffering from Alzheimer-type dementia were administered with EPA at a daily dose of 900 mg for 12 months, and the symptoms were observed (number of the evaluated case: 22), "administration of EPA to the patients of Alzheimer-type dementia resulted in the improvement of the cognitive skill for 3 to 6 months. However, after this period, the cognitive skill declined with the natural prognosis of the disease" (page 27, right column) .

[0005] This document, however, does not disclose or indicate excellent effects on the Alzheimer-type dementia achieved by the combination of the ω-3 polyunsaturated fatty acid and thyroid hormone.

[0006] [Non-patent document]
Dementia Japan, 2001, vol. 15, pp. 21-29.

Disclosure of the Invention

[0007] In view of the situation as described above, an object of the present invention is to provide a highly safe preventive or therapeutic drug for Alzheimer-type dementia which can replace the conventional therapies currently used for Alzheimer-type dementia or which can be used together with the conventional therapy to realize high therapeutic effects.

[0008] The inventors of the present invention carried out an intensive study on the preventive or therapeutic drug for Alzheimer-type dementia, and found that use of a combination of an ω-3 polyunsaturated fatty acid and a thyroid hormone exhibits excellent therapeutic effects for Alzheimer-type dementia as well as high safety. The present invention has been completed on the basis of such finding.

[0009] The preventive or therapeutic drug for Alzheimer-type dementia wherein an ω-3 polyunsaturated fatty acid is used in combination with a thyroid hormone has significant therapeutic effects for the Alzheimer-type dementia while it exhibits no adverse events, and accordingly, it should provide a highly effective preventive or therapeutic drug for Alzheimer-type dementia with high safety.

Best Mode for Carrying out the Invention

[0010] Next, the present invention is described in detail.
According to an aspect of the present invention, the present invention provides a preventive or therapeutic drug for Alzheimer-type dementia wherein an ω-3 polyunsaturated fatty acid is used in combination with a thyroid hormone.
According to another aspect of the present invention, the present invention provides a food having a preventive or therapeutic effect for Alzheimer-type dementia wherein an ω-3 polyunsaturated fatty acid is used in combination with a thyroid hormone.
A polyunsaturated fatty acid is defined as a fatty acid having two or more carbon-carbon double bonds in the molecule, and the polyunsaturated fatty acids are further grouped by the position of the double bond into ω-3, ω-6, and other polyunsaturated fatty acids. Exemplary ω-3 polyunsaturated fatty acids include α-linolenic acid, EPA, and docosahexaenoic acid (hereinafter abbreviated as DHA). The polyunsaturated fatty acid used in the present invention may be either a synthetic or a natural polyunsaturated fatty acid, or a natural oil containing such polyunsaturated fatty acids. Synthetic products include those which have been produced by chemical synthesis, and semi-synthetic products which have been produced by microorganisms and then subjected to esterification, ester exchange, or the like. The natural products may be either those extracted from a natural oil containing polyunsaturated fatty acids by a known means or those which have been further processed to produce a crude product or further purified products. Salts of an ω-3 polyunsaturated fatty acid as well as derivatives such as ester, amide, phospholipid, monoglyceride, diglyceride, and triglyceride of a polyunsaturated fatty acid are also included within the ω-3 polyunsaturated fatty acid used in the present invention.

[0011] The ω-3 polyunsaturated fatty acid used in the present invention is preferably at least one member selected from EPA, DHA, and α-linolenic acid. Still more preferably, the ω-3 polyunsaturated fatty acid is EPA, DHA, or a mixture thereof, and even more preferably, the ω-3 polyunsaturated fatty acid is ethyl icosapentate (hereinafter abbreviated as EPA-E), ethyl docosahexaenoate (hereinafter abbreviated as DHA-E), or a mixture thereof. Most preferably, the ω-3 polyunsaturated fatty acid is EPA-E. In Japan, a soft capsule preparation containing high purity EPA-E (trade name Epadel, manufactured by MOCHIDA PHARMACEUTICAL CO., LTD.) is commercially available as a therapeutic drug for arteriosclerosis obliterans (ASO) or hyperlipidemia, and this product can be used. An example of the mixture of EPA-E and DHA-E is Omacor (a soft capsule containing about 46% by weight of EPA-E and about 38% by weight of DHA-E manufactured by Ross Products), which is commercially available in the U.S. and the like as a therapeutic agent for hypertriglyceridemia, and which may be used in the present invention. Also preferred are the embodiments wherein the ω-3 polyunsaturated fatty acid is in the form of a purified fish oil as well as the embodiments wherein the ω-3 polyunsaturated fatty acid is at least one member selected from monoglyceride, diglyceride, and triglyceride.

[0012] The purity of the ω-3 polyunsaturated fatty acid used in the composition of the present invention, namely, content of the ω-3 polyunsaturated fatty acid in the entire fatty acid is not particularly limited. However, the purity is preferably at least 25% by weight, more preferably at least 50% by weight, still more preferably at least 70% by weight, and still more preferably at least 85% by weight, and most preferably, the purity of the polyunsaturated fatty acid is such that it is substantially free from fatty acid components other than the ω-3 polyunsaturated fatty acid.

[0013] ω-3 polyunsaturated fatty acid is easily oxidized, and therefore, simultaneous incorporation of an effective amount of an antioxidant such as butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, gallic acid, a pharmaceutically acceptable quinone, or α-tocopherol is desirable.

[0014] The thyroid hormone used in the present invention is not particularly limited as long as it exhibits the effects intended in the present invention. Exemplary thyroid hormones include levothyroxine and liothyronine, and the preferred is levothyroxine sodium (trade name, Thyradin S, manufactured by ASKA Pharmaceutical Co., Ltd.). It is to be noted that substantially same effects are realized by using a growth hormone (for example, somatropin) instead of the thyroid hormone.

[0015] The preventive or therapeutic drug for Alzheimer-type dementia of the present invention may be administered either by solely administering the effective components (possibly with other inevitable components remaining after the purification), or by forming an adequate pharmaceutical preparation with a carrier or a medium commonly used in the art such as an excipient, a binder, a lubricant, a colorant, or a flavor, optionally with sterilized water or a vegetable oil, or further with a non-toxic organic solvent or a non-toxic solubilizer (for example, glycerin or propylene glycol), an emulsifier, a suspending agent (for example, Tween 80 and or arabic solution), an isotonic agent, a pH adjusting agent, a stabilizer, a soothing agent. The food having a preventive or therapeutic effects for Alzheimer-type dementia of the present invention may also be prepared either with solely the effective component (possibly with other inevitable components remaining after the purification), or in combining with a carrier or a medium commonly used in the art as in the case of the preventive or therapeutic drug for Alzheimer-type dementia. Exemplary preferable foods include supplement, nutraceutical, food with nutrient function claims, food for specified health uses, and health food.

[0016] The pharmaceutical preparation may be administered orally, intravenously, intraarterially, by inhalation, endorectally, intravaginally, or externally in the dosage form of a tablet, a capsule, a microcapsule, granules, fine granules, a powder, an oral liquid, a suppository, a syrup, an inhalant, an ointment, an injection (emulsion, suspension, or non-aqueous), or an injection in the form of emulsion or suspension which has been prepared from a solid injection immediately before the administration. The preferred is the oral administration by encapsulating in a capsule such as a soft capsule or a microcapsule. Also preferred is intravenous or intraarterial administration in the form of an injection (emulsion, suspension, or non-aqueous) or an injection in the form of emulsion or suspension which has been prepared from a solid injection immediately before the administration.

[0017] The dose of the ω-3 polyunsaturated fatty acid of the preventive or therapeutic drug for Alzheimer-type dementia of the present invention may be an effective amount to exhibit the intended behavior which may be adequately adjusted by the dosage form, administration route, frequency of administration per day, seriousness of the symptom, body weight, age, and the like. When ethyl icosapentate is orally administered, a dose in terms of EPA-E is typically 100 to 9,000 mg/day, preferably 300 to 6,000 mg/day, and more preferably 300 to 2,700 mg/day which may be administered in 2 to 3 divided doses, or if desired in a single dose or in several divided doses.

[0018] The dose of the thyroid hormone of the preventive or therapeutic drug for Alzheimer-type dementia of the present invention may be an effective amount to exhibit the intended behavior which may be adequately adjusted by the dosage form, administration route, frequency of administration per day, seriousness of the symptom, body weight, age, and the like. When levothyroxine sodium is orally administered, a dose in terms of levothyroxine sodium of 25 to 200 µg/day may be administered once a day. Such dose, however, may be administered in several divided doses.

[0019] The combination of the daily dose of the EPA-E and the daily dose of the levothyroxine sodium is not particularly limited. However, this combination is preferably one of (1) 1,800 to 2,700 mg/day of EPA-E and 25 to 200 µg/day of levothyroxine sodium, (2) 1,800 to 2,700 mg/day of EPA-E and 25 to 100 µg/day of levothyroxine sodium, (3) 300 to 600 mg/day of EPA-E and 25 to 200 µg/day of levothyroxine sodium, and (4) 300 to 600 mg/day of EPA-E and 25 to 100 µg/day of levothyroxine sodium.

[0020] The a preventive or therapeutic drug for Alzheimer-type dementia of the present invention characterized by the combined use of an ω-3 polyunsaturated fatty acid and a thyroid hormone may be in the form of 1) combined taking of the both drugs, namely, simultaneous or separate taking of the drug containing the ω-3 polyunsaturated fatty acid and the drug containing the thyroid hormone; 2) a combined drug, namely, a drug prepared by incorporating both of the ω-3 polyunsaturated fatty acid and the thyroid hormone, and 3) a kit containing both drugs, namely, a set prepared by combining a unit dose (single dose, daily dose, etc.) of the drug containing an ω-3 polyunsaturated fatty acid and the drug containing a thyroid hormone. The preventive or therapeutic drug for Alzheimer-type dementia of the present invention include the drug containing an ω-3 polyunsaturated fatty acid and a thyroid hormone as its only effective components, namely, the drug prepared by combining an ω-3 polyunsaturated fatty acid and a thyroid hormone; and also, a preventive or therapeutic drug for Alzheimer-type dementia further comprising an effective component other the ω-3 polyunsaturated fatty acid and the thyroid hormone.

[0021] The preventive or therapeutic drug for Alzheimer-type dementia of the present invention may be used with any one of the conventional therapeutic drug for Alzheimer-type dementia as typically represented by donepezil (trade name Aricept: manufactured by Eisai Co.,Ltd.). Combination with the donepezil enables improvement of the Alzheimer-type dementia whose symptoms could not be sufficiently improved by donepezil alone. Such combination also enables use of the donepezil at a reduced dose.

[0022] The preventive or therapeutic drug for Alzheimer-type dementia of the present invention wherein an ω-3 polyunsaturated fatty acid is used in combination with a thyroid hormone also includes the case in which a patient of Alzheimer-type dementia who is administered with an ω-3 polyunsaturated fatty acid (1) for the purpose of treating hyperlipidemia or ASO, (2) in the expectation of antiarteriosclerotic action, or (3) in the expectation of preventing onset of the cardiovascular event or cerebrovascular event, and in particular, a patient whose improvement of the symptom of the Alzheimer-type dementia is insufficient is further administered with a thyroid hormone. Also included in the present invention is the case in which a patient of Alzheimer-type dementia who is administered with a thyroid hormone, and in particular, a patient whose improvement of the symptom of the Alzheimer-type dementia is insufficient is further administered with a drug containing an ω-3 polyunsaturated fatty acid, and in particular, a drug containing EPA-E.

[0023] The severity of the Alzheimer-type dementia to be treated by the therapeutic drug for Alzheimer-type dementia characterized by the use of a combination of an ω-3 polyunsaturated fatty acid and a thyroid hormone of the present invention is not particularly limited. According to Reisberg, average score of Hasegawa Dementia Scale (wherein the score of up to 20 corresponds to "doubt of dementia" on a scale of 30) in each severity is such that 19.1 for slight dementia, 15.4 for moderate dementia, 10.7 for slightly advanced dementia, and 4.0 for advanced dementia.

Examples

[0024] Next, the present invention is described in further detail by referring to the Examples, which by no means limit the scope of the present invention.

(Example)

[Subject and method]

[0025] 14 patients (6 males and 8 females in their fifties to eighties) diagnosed with Alzheimer-type dementia but having no history of cerebral infarction and not suffering from primary diseases of dementia such as hypothyroidism were administered with ethyl icosapentate (trade name Epadel; manufactured by Mochida Pharmaceutical Co.,Ltd.; abbreviated as "EPA-E" in the Table) at a daily dose of 300 to 600 mg for 2 months, and then, also with levothyroxine sodium (trade name thyradin S; manufactured by ASKA Pharmaceutical Co., Ltd.; abbreviated as "T4" in the Table) at a daily dose of 50 to 100 µg for 4 months in addition to the ethyl icosapentate. Each patient was evaluated for the improvement of the dementia by Hasegawa Dementia Scale at the start of the test, 2 months after the start of the test (2 months from the start of administering ethyl icosapentate), and 6 months after the start of the test (4 months after the start of the combined administration of the ethyl icosapentate and the levothyroxine sodium).

[Results]

[0026] The results for each case are shown in Table 1. The average score of the Hasegawa Dementia Scale is shown in Table 3 together with the average score of Reference Examples. As shown in Table 1, when the change in symptoms was observed after the test period of 6 months, improvements such as willingness, refection, increase in the habitat, and lucidity were noted. In addition, improvement in the score of Hasegawa Dementia Scale was noted in substantially all cases. Average score of the Hasegawa Dementia Scale at the start of the test was 10.0, and this average score increased to as high as 16.8 at the end of the test period (6 months after the start of the test). Improvement in the symptoms was noted also in somewhat advanced to considerably advanced dementia. No adverse event was noted.

[0027] 

[Table 1]

Table 1: Alzheimer-type dementia
No.	Gender	Age	Diagnosis	Chief complaint, etc.	Dementia history (year)	Dose of EPA-E mg/day	Dose of T4 ug/day	Hasegawa Dementia Scale			Side effects	Concomitant drug	Change in symptom
								At the start	After 2 months	After 6 months
1	Female	60'	Dementia	Forgetfulness	5	300	100	8	9	18	0	None
2	Female	50'	Diabetes mellitus, dementia	Forgetfulness	7	600	100	14	14	18	0	Insulin	Willingness
3	Male	70'	Dementia	Forgetfulness	5	600	50	4	7	14	0	None
4	Female	60'	Dementia	Anorexia	3	300	100	13	14	16	0	None
5	Female	60'	Dementia	Anorexia	6	600	100	6	8	15	0	None	Willingness
6	Female	70'	Diabetes mellitus, dementia	Headache	2	600	100	8	11	18	0	SU drug
7	Female	60'	Diabetes mellitus, dementia	Diabetes treatment	4	600	100	8	11	17	0	Insulin	Refection
8	Male	60'	Dementia, adrenal insufficiency	Dystropy	1	300	100	12	12	14	0	Glucocorticoid
9	Male	70'	Dementia	Forgetfulness	7	600	50	16	17	22	0	None	Refection
10	Male	60'	Diabetes mellitus, dementia	Diabetes treatment	15	300	100	9	11	14	0	SU drug
11	Female	70'	Dementia	Forgetfulness	5	600	50	10	13	20	0	None	Increase in the habitat
12	Male	80'	Dementia	Forgetfulness	5	300	50	11	10	16	0	None
13	Female	70'	Hypertension, dementia	Hypertension treatment	6	600	100	14	15	20	0	Ca antagonist	Lucidity
14	Male	60'	Diabetes mellitus, dementia	Diabetes treatment	2	300	100	7	7	13	0	Insulin	Refection

(Reference Example)

[Subject and method]

[0028] 10 patients (6 males and 4 females in their fifties to eighties) diagnosed with cerebrovascular dementia but having the history of cerebral infarction were administered with ethyl icosapentate (trade name Epadel; manufactured by Mochida Pharmaceutical Co.,Ltd.; abbreviated as "EPA-E" in the Table) at a daily dose of 300 to 600 mg for 2 months, and then, also with levothyroxine sodium (trade name thyradin S; manufactured by ASKA Pharmaceutical Co., Ltd.; abbreviated as "T4" in the Table) at a daily dose of 50 to 100 µg for 4 months in addition to the ethyl icosapentate. Each patient was evaluated for the improvement of the dementia by Hasegawa Dementia Scale at the start of the test, 2 months after the start of the test (2 months from the start of administering ethyl icosapentate), and 6 months after the start of the test (4 months after the start of the combined administration of the ethyl icosapentate and the levothyroxine sodium).

[Results]

[0029] The results for each case are shown in Table 2. The average score of the Hasegawa Dementia Scale is shown in Table 3 together with the average score of Examples. As shown in Table 2, average score of the Hasegawa Dementia Scale was in slightly improving trend in substantially all cases after 6 months although the improvement was not significant. In the observation of the symptom, refection was noted in one case (10%). The case that showed such improvement of the symptom was the case in which highest score of Hasegawa Dementia Scale had been observed at the start of the test. No adverse event was noted.

[0030] 

[Table 2]

Table 2: Cerebrovascular dementia
No.	Gender	Age	Diagnosis	Chief complaint, etc.	Dementia history (year)	Dose of EPA-E mg/day	Dose of T4 µg/day	Hasegawa Dementia Scale			Side effects	Concomitant drug	Change in symptom
								At the start	After 2 months	After 6 months
1	Male	60'	Cerebral infarction, diabetes mellitus, dementia	Disorientation	2	600	100	8	9	11	0	Insulin
2	Female	60'	Cerebral infarction, dementia	Paralysis	2	300	100	12	13	14	0	None
3	Male	50'	Cerebral infarction, dementia	Slump	1	600	100	14	15	18	0	None	Refection
4	Male	60'	Cerebral infarction, dementia	Forgetfulness	4	600	100	10	11	12	0	None
5	Female	70'	Cerebral infarction, dementia	Disorientation	9	600	50	10	12	14	0	None
6	Male	60'	Cerebral infarction, diabetes mellitus, dementia	Weight loss	6	300	100	10	10	11	0	Insulin
7	Female	70'	Cerebral infarction, dementia	Weight loss	1.5	300	50	11	12	13	0	None
8	Female	80'	Cerebral infarction, dementia	Disorientation	10	300	50	9	10	11	0	None
9	Male	70'	Cerebral infarction, dementia	Paralysis	5	600	50	9	9	13	0	None
10	Male	60'	Cerebral infarction, diabetes mellitus, dementia	Insomnia	3	600	100	11	11	14	0	SU drug

[0031] 

[Table 3]

Table 3: Score of the Hasegawa Dementia Scale (average ± standard deviation, range)
	At the start of the test	2 months after the start of the test	6 months after the start of the test
Examples (Alzheimer-type dementia)	10.0±3.5 (6 - 16)	11.4±3.0 (7 - 17)	16.8±2.7 (13 - 22)
Referential Examples (Cerebrovascular dementia)	10.4±1.7 (9 - 14)	11.2±1.9 (9 - 15)	13.1±2.1 (11 - 18)

[0032] As demonstrated by the results of Table 3, while sole administration of ethyl icosapentate at a dose of 300 to 600 mg/day for 2 months resulted in no substantial change in the scores of the Hasegawa Dementia Scale of the patients suffering from Alzheimer-type dementia, simultaneous administration of levothyroxine sodium for the subsequent 4 months at a dose of 50 to 100 µg/day with the ethyl icosapentate resulted in the significant improvement in the scores of the Hasegawa Dementia Scale of the patients suffering from Alzheimer-type dementia. On the other hand, as demonstrated by the results of the Referential Example in Table 3, only slight improvement in the score of Hasegawa Dementia Scale was realized in test of the simultaneous administration of the ethyl icosapentate at 300 to 600 mg/day and the levothyroxine sodium at 50 to 100 µg/day for the patients of cerebrovascular dementia.

[0033] As demonstrated above, the combination of an ω-3 polyunsaturated fatty acid and a thyroid hormone, and in particular, the combination of the EPA-E and the levothyroxine sodium has a significant therapeutic effects for Alzheimer-type dementia with no adverse event, and such combination would constitute a highly effective and safe preventive or therapeutic drug for Alzheimer-type dementia. In the meanwhile, since the daily dose of the EPA-E for present indication, namely, hyperlipidemia or arteriosclerosis obliterans (ASO) is 1800 to 2700 mg, the results confirmed that EPA-E exhibits its effect at a dose lower than the usual dose when combined with the levothyroxine sodium. In addition, since usual dose (maintenance dose) of the levothyroxine sodium for present indication is 100 to 400 µg/day, the levothyroxine sodium exhibits was also confirmed to exhibit its effect at the lower limit of the usual dose or at an even lower dose.

Claims

1. A preventive or therapeutic drug for Alzheimer-type dementia wherein an ω-3 polyunsaturated fatty acid is used in combination with a thyroid hormone.

2. The preventive or therapeutic drug according to claim 1 wherein the ω-3 polyunsaturated fatty acid is icosapentaenoic acid, docosahexaenoic acid, or a mixture of icosapentaenoic acid and docosahexaenoic acid.

3. The preventive or therapeutic drug according to claim 1 or 2 wherein the ω-3 polyunsaturated fatty acid is ethyl icosapentate, ethyl docosahexaenoate, and a mixture thereof.

4. The preventive or therapeutic drug according to any one of claims 1 to 3 wherein the ω-3 polyunsaturated fatty acid is ethyl icosapentate.

5. The preventive or therapeutic drug according to any one of claims 1 to 4 wherein the thyroid hormone is levothyroxine.